Thieno[2,3-b]pyridine Ligands for mGluR1/5 Selectivity
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Solution Overview
Problem
Current compounds do not effectively target and modulate mGluR1 and mGluR5 receptors, which are implicated in various CNS disorders, including stroke, epilepsy, and pain, leading to excessive glutamate-induced neuronal excitation and associated pathologies.
Innovation Solution
Development of new mGluR1 and mGluR5 receptor subtype preferring ligands of formula (I), including their salts and hydrates, which are synthesized through specific processes and used in pharmaceutical compositions for therapeutic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing compounds are used to target mGluR1 and mGluR5 receptors, then receptor modulation is achieved, but potency and selectivity are insufficient
Solution Approach 1:
The patent applies parameter changes by systematically modifying molecular parameters of the compound structure, including substituting different groups at specific positions (R1-R6), changing stereochemistry, and adjusting molecular weight and lipophilicity parameters to achieve high potency and selectivity for mGluR1 and mGluR5 receptors
Solution Approach 2:
The patent creates composite molecular structures by combining thieno[2,3-b]pyridine core with various functional groups and substituents (sulfonyl, carbonyl, hydroxyl, amino groups) to produce compounds that simultaneously bind to multiple receptor subtypes with high affinity and selectivity
2Reliability
If high potency ligands are developed for mGluR1 and mGluR5, then therapeutic efficacy is improved, but synthesis complexity increases
Solution Approach 1:
The patent segments the synthesis process into modular steps, starting from commercially available thieno[2,3-b]pyridine derivatives and systematically building up the complex molecules through sequential coupling reactions, allowing for optimized synthesis routes for each compound class
Solution Approach 2:
The patent employs intermediate compounds and reagents in the synthesis process, using protected groups and temporary modifications that are later removed or transformed, which simplifies the overall synthesis by breaking down complex transformations into manageable steps
3Object-affected harmful factors
If selective mGluR1 and mGluR5 antagonists are used, then neuronal excitation is reduced, but off-target effects may occur
Solution Approach 1:
The patent applies local quality by introducing specific functional groups and substituents at particular positions on the molecular structure that create selective interactions with mGluR1 and mGluR5 receptors, while avoiding interactions with other receptor subtypes through precise spatial arrangement of functional groups
Data Source
AI summary
The present invention relates to new mGluRl and mGluR5 receptor subtype preferring ligands of formula (I) wherein X represents a group selected from SO, SO2; Y represents a group selected from (CH2)n, NH, NHCH2; n is an integer of 0 to 1; Z is H or monosubstituted by alkyl, nitro, halogen, alkoxy, trifluoromethyl, cyano, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxyl, alkylsulfonylamino; R1 is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R2 is an optionally substituted phenyl, heterocyclyl, or NR3R4 group wherein R3 and R4 are independently selected from the group of hydrogen and an optionally substituted alkyl, or R3 and R4 together with the N atom to which they are attached form an optionally substituted C5-7 heterocyclyl group, containing one or more heteroatom(s), or NH-CO-NR5R6 group, wherein R5 and R6 are independently selected from the group of hydrogen and an optionally substituted alkyl, or R5 and R6 together with the N atom to which they are attached form an optionally substituted C5-7 heterocyclyl group, containing one or more heteroatom(s); and/or hydrates and/or solvates and/or pharmaceutically acceptable salts thereof formed with acids or bases, to the processes for producing the same, to pharmaceutical compositions containing the same and to their use in therapy and/or prevention of pathological conditions which require the modulation of mGluRl and mGluR5 receptors such as neurological disorders, psychiatric disorders, acute and chronic pain, neuromuscular dysfunctions of the lower urinary tract and gastrointestinal disorders.